Substituted 9-(1-O- or 3-O-monosubstituted or 1,3-di-O-substituted propoxymethyl)purines as antiviral agents

ABSTRACT

Compounds useful as antiviral agents are defined by the following formula: ##STR1## wherein R 1  is hydrogen, --C(Y)OR 7  or --C(O)NHR 7  wherein R 7  is alkyl of one to twelve carbon atoms, alkenyl of two to twelve carbon atoms, cyclopentyl, cyclohexyl, phenyl or benzyl; 
     R 2  is --C(Y)OR 7  or --C(O)NHR 7  wherein R 7  is as defined above; 
     Y is oxygen or sulfur; 
     R 3  is hydrogen, halo, thio, lower alkylthio of one to six carbon atoms, azido, NR 9  R 10  wherein R 9  and R 10  are independently hydrogen or lower alkyl of one to six carbon atoms or --NHC(O)R 8  wherein R 8  is hydrogen, alkyl of one to nineteen carbon atoms or 1-adamantyl; and 
     (a) R 6  is hydrogen, halo, lower alkoxy of one to six carbon atoms, azido, thio, lower alkylthio of one to six carbon atoms, --NR 9  R 10  wherein R 9  and R 10  are as defined above or --NHC(O)R 8  wherein R 8  is as defined above and R 4  together with R 5  is a bond; or 
     (b) R 5  together with R 6  is a keto group and R 4  is hydrogen.

This is a division of co-pending application Ser. No. 406,583, filedAug. 9, 1982, now U.S. Pat. No. 4,556,659.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to substituted 9-(1-0- or 3-0-monosubstituted or1,3-di-0-substituted-2-propoxymethyl)purines which are useful asantiviral agents. The invention also relates to a pharmaceuticalcomposition containing the above compounds in combination with asuitable non-toxic excipient, the composition being useful in combattingviral infections. The invention also relates to a process for preparingthe compounds of the invention.

2. Related Disclosure

Viral infections are widespread and result in a wide variety ofsymptoms. Some viral infections are easily overcome by the body'sdefense mechanism, but when this defense mechanism is impaired theseinfections can lead to permanent damage, e.g., blindness, and even todeath. One such family of viruses which may cause serious infections isthe herpes virus group.

The drugs presently used to treat viral infections are ineffective inmany cases or, if effective, are needed in large and/or continuousdosages which produce serious side-effects and/or toxicity. Thereforethere is a need for an effective antiviral agent which is effective atlower dosages than the presently available drugs, thus diminishing thechance of possible side-effects and toxicity.

U.S. Pat. No. 4,199,574 discloses compounds represented by the followinggeneric formula: ##STR2## wherein X is sulphur or oxygen, R¹ ishydrogen, halogen, hydroxy, alkoxy, azide, thio, alkylthio, amino,alkylamino or dialkylamino; R² is hydrogen, halogen, alkylthio,acylamino, amino or azide; R³ is hydrogen, straight or branch chain orcyclic alkyl, hydroxyalkyl, benzyloxyalkyl or phenyl; R⁴ is hydrogen,hydroxy or alkyl; R⁵ is hydrogen, hydroxy, amino, alkyl, hydroxyalkyl,benzyloxy, benzoyloxy, benzoyloxymethyl, sulphamoyloxy, phosphate,carboxypropiamyloxy, straight chain or cyclic acyloxy having from 1 to 8carbon atoms e.g., acetoxy or substituted carbamoyl group of formulaNHCO--Z wherein Z is alkyl, aryl or aralkyl optionally substituted byone or more of sulphonyl, amino, carbamoyl or halogen; R⁶ is hydrogen oralkyl, provided that when X is oxygen and R², R³, R⁴, and R⁶ arehydrogen, R¹ is not amino or methylamino when R⁵ is hydrogen or hydroxy,or a salt thereof.

The class of compounds represented by the above formula and thepharmaceutically acceptable acid addition salts thereof are described toexhibit antiviral activity. See also Tetrahedron Letters, 21, 327-30(1980) and U.S. Pat. No. 4,294,831.

SUMMARY OF THE INVENTION

It has now been discovered that substituted 9-(1-0- or3-0-monosubstituted or1,3-di-0-substituted-1,3-dihydroxy-2-propoxymethyl)purines areparticularly active antiviral agents.

The first aspect of the present invention is the compound of thefollowing formula: ##STR3## wherein

R¹ is hydrogen, --C(Y)OR⁷ or --C(O)NHR⁷ wherein R⁷ is alkyl of one totwelve carbon atoms, alkenyl of two to twelve carbon atoms, cyclopentyl,cyclohexyl, phenyl or benzyl;

R² is --C(Y)OR⁷ or --C(O)NHR⁷ wherein R⁷ is as defined above;

Y is oxygen or sulfur;

R³ is hydrogen, halo, thio, lower alkylthio of one to six carbon atoms,azido, NR⁹ R¹⁰ wherein R⁹ and R¹⁰ are independently hydrogen or loweralkyl of one to six carbon atoms or --NHC(O)R⁸ wherein R⁸ is hydrogen,alkyl of one to nineteen carbon atoms or 1-adamantyl; and

(a) R⁶ is hydrogen, halo, lower alkoxy of one to six carbon atoms,azido, thio, lower alkylthio of one to six carbon atoms, --NR⁹ R¹⁰wherein R⁹ and R¹⁰ are as defined above or --NHC(O)R³ wherein R⁸ is asdefined above and R⁴ together with R⁵ is a bond; or

(b) R⁵ together with R⁶ is a keto group and R⁴ is hydrogen.

Another aspect of the invention relates to a pharmaceutical compositionfor antiviral use comprising a compound of the instant invention and asuitable carrier.

A further aspect of the invention is a method of treating viralinfections consisting of administering a compound of the presentinvention or a composition containing same.

Yet another aspect of the invention is a process for preparing thecompounds of formula (I) which comprises

(a) reacting a dihydroxy compound of formula (X) or (XIV) wherein A ishydrogen (infra) with a dicarbonate of the formula (R⁷ OC(O))₂ O whereinR⁷ is as defined above; or

(b) reacting an intermediate of the formula ##STR4## wherein W ishydrogen or 1-carbonylimidazole and Wa is 1-carbonylimidazole with theappropriate alcohol or amine; or

(c) reacting a compound of formula (XV)(supra) wherein W is hydrogen or1-thiocarbonylimidazole and Wa is 1-thiocarbonylimidazole with theappropriate alcohol; or

(d) reacting the trityl protected derivative of formula (X) or (XIV)wherein A is hydrogen with a hydrocarbyloxycarbonyl chloride of theformula ClC(O)OR⁷ and removing the trityl protecting groups.

Yet another aspect of the invention is the novel compounds of formula(XV) which are useful as antiviral agents and as intermediates for thepreparation of compounds of formula (I).

DETAILED DESCRIPTION AND PREFERRED EMBODIMENTS

As used in the specification and appended claims, unless specified tothe contrary, the following terms have the meaning indicated.

The term "hydrocarbyl" refers to substituents consisting solely ofcarbon and hydrogen. Examples of hydrocarbyl groups are alkyl, alkenyl,cyclopentyl, cyclohexyl, phenyl and benzyl.

The term "alkyl" refers to a straight or branched chain monovalentsubstituent consisting solely of carbon and hydrogen, containing nounsaturation and having one to twelve carbon atoms. Examples of alkylare methyl, ethyl, propyl, t-butyl, hexyl, n-octyl, n-decyl, andn-dodecyl. The term "lower alkyl" refers to alkyl groups as definedabove but containing one to six carbon atoms. The term "alkenyl" refersto a straight or branched chain monovalent substituent consisting solelyof carbon and hydrogen, containing one double bond and having two totwelve carbon atoms. Examples of "alkenyl" are ethenyl, propenyl,i-butenyl, pentenyl, hexenyl and n-decenyl. The term "1-adamantyl"refers to the following ring structure. ##STR5## "Lower alkoxy" refersto "lower alkyl-O-" wherein "lower alkyl" is as defined above. Examplesof "lower alkoxy" are methoxy, ethoxy, propoxy, i-butoxy, pentyloxy andn-hexyloxy. The term "lower alkylthio" refers to "lower alkyl-S-"wherein "lower alkyl" is as defined above. Examples of "lower alkylthio"are methylthio, n-propylthio, n-butylthio and n-pentylthio. "Thio"refers to --SH. "Amino" refers to --NH₂. "Azido" refers to N₃. "Halo"refers to fluoro, chloro and bromo. "Thiocarbonyl" refers to ##STR6##

Compounds of formula (I) wherein R¹ is hydrogen contain an assymetriccarbon atom. Accordingly, these compounds may be prepared in eitheroptically active form or as a racemic mixture. Unless otherwisespecified, the compounds of formula (I) described herein are all in theracemic form. However, the scope of the subject invention is not to beconsidered limited to the racemic form, but to encompass the individualoptical isomers of the compounds of formula (I).

It is to be understood that the definition of R⁵ together with R⁶ asketo includes the tautomeric hydroxy form but for convenience the ketoform will be used to represent both tautomeric forms.

A preferred group of compounds of formula (I) is that wherein R³ isamino, R⁴ is hydrogen and R⁵ together with R⁶ is keto (compounds offormula (Ia) infra). Another preferred group of compounds of formula (I)is that wherein R³ is hydrogen or amino, R⁶ is hydrogen, thio or NH₂ andR⁴ together with R⁵ is a bond with the proviso that R³ and R⁶ are notboth hydrogen. A preferred subgroup within these groups is that whereinR¹ and R² are independently --C(O)OR⁷ and R⁷ is lower alkyl,particularly methyl.

UTILITY AND ADMINISTRATION

The subject compound of formula (I) and the pharmaceutically acceptablesalts thereof exhibit potent antiviral activity when administered towarm blooded and cold blooded animals, particularly mammals, birds, andfish, but most particularly humans. For example, the compound of thepresent invention exhibits excellent activity against Herpes Simplexvirus I and II and related viruses such as cytomegalovirus, Epstein-Barrvirus and varicella Zoster virus.

Pharmaceutical compositions, both veterinary and human, containing thesubject compound appropriate for antiviral use are prepared by methodsand contain excipients which are well known in the art. A generallyrecognized compendium of such methods and ingredients is Remington'sPharmaceutical Sciences by E. W. Martin, (Mark Publ. Co., 15th Ed.,1975).

The compound of the invention may be administered parenterally (forexample, by intraveneous, subcutaneous, intraperitoneal or intramuscularinjection), orally, topically, rectally or intranasally.

The compositions are administered orally or parenterally at dose levels,calculated as the free base, of about 0.1 to 300 mg/kg, preferably 1.0to 30 mg/kg of mammal body weight, and are used in man in a unit dosageform, administered one to five times daily in the amount of 1 to 500 mgper unit dose. For oral administration, fine powders or granules maycontain diluting, dispersing and/or surface active agents, and may bepresented in a draught, in water or in a syrup; in capsules or sachetsin the dry state or in a non-aqueous solution or suspension, whereinsuspending agents may be included; in tablets, wherein binders andlubricants may be included; in a suspension in water or a syrup; or inan aerosol. Where desirable or necessary, flavoring, preserving,suspending, thickening or emulsifying agents may be included. Tabletsand granules are preferred, and these may be coated. The amount ofcompound of formula (I) in the formulation may vary from 0.1 percentweight (% w) to 99% w or more of the compound based on the totalformulation and about 1% w to 99.9% w excipient. Preferably the compoundis present at a level of 10%-95% w.

For parenteral administration or for administration as drops, as for eyeinfections, the compounds may be presented in aqueous solution in aconcentration of from about 0.1 to 10%, more preferably about 0.1 to 7%.The solution may contain antioxidants, buffers, and other suitableadditives.

Alternatively for infections of the eye, or other external tissues, e.g.mouth and skin, the compositions are preferably applied to the infectedpart of the body of the patient topically as an ointment, cream, aerosolor powder, preferably an an ointment or cream. The compounds may bepresented in an ointment, for instance with a water soluble ointmentbase, or in a cream, for instance with an oil in water cream base, in aconcentration of from about 0.01 to 10%; preferably 0.1 to 7%, mostpreferably about 3.0% w/v. Additionally, viral infections may be treatedby use of a sustained release drug delivery system as is described inU.S. Pat. No. 4,217,898.

For aerosol administration, the active ingredient is preferably suppliedin finely divided form along with a surfactant and a propellant. Typicalpercentages of active ingredients are 0.01 to 20% by weight, preferably0.04 to 1.0%.

Surfactants must, of course, be non-toxic, and preferably soluble in thepropellant. Representative of such agents are the esters or partialesters of fatty acids containing from 6 to 22 carbon atoms, such ascaproic, octanoic, lauric, palmitic, stearic, linoleic, linolenic,olestearic and oleic acids with an aliphatic polyhydric alcohol or itscyclic anhydride such as, for example, ethylene glycol, glycerol,erythritol, arabitol, mannitol, sorbitol, the hexitol anhydrides derivedfrom sorbitol (the sorbitan esters sold under the trademark "Spans") andthe polyoxyethylene and polyoxypropylene derivatives of these esters.Mixed esters, such as mixed or natural glycerides may be employed. Thepreferred surface-active agents are the oleates or sorbitan, e.g., thosesold under the trademarks "Arlacel C" (Sorbitan sesquioleate), "Span 80"(sorbitan monooleate) and "Span 85" (sorbitan trioleate). The surfactantmay constitute 0.1-20% by weight of the composition, preferably 0.25-5%.

The balance of the composition is ordinarly propellant. Liquefiedpropellants are typically gases at ambient conditions, and are condensedunder pressure. Among suitable liquefied propellants are the loweralkanes containing up to five carbons, such as butane and propane; andpreferably fluorinated or fluorochlorinated alkanes, such as are soldunder the trademark "Freon." Mixtures of the above may also be employed.

In producing the aerosol, a container equipped with a suitable valve isfilled with the appropriate propellant, containing the finely dividedactive ingredient and surfactant. The ingredients are thus maintained atan elevated pressure until released by action of the valve.

The compounds of the present invention or compositions containing sameare also useful in treating non-human mammals, birds, e.g., chickens andturkeys, and cold-blooded animals, e.g., fish. For example, thecompounds of the present invention and compositions containing sameexhibit antiviral activity against the following non-human viruses:

Sciruid herpesvirus 1

Cavlid herpesvirus 1

Lagomorph herpesvirus 1

Phasianid herpesvirus 1

Phasianid herpesvirus 2 (Marek's disease)

Turkey herpesvirus 1

Anatid herpesvirus 1

Catfish herpesvirus 1

Equid herpesvirus 3

Bovid herpesvirus 1

Bovid herpesvirus 2

Bovid herpesvirus 3

Bovid herpesvirus 4

Pig herpesvirus 1

Pig herpesvirus 2

Murid herpesvirus 1

Cebid herpesvirus 1

Cebid herpesvirus 2

Tupaiid herpesvirus 1

Canine herpesvirus 1

Feline herpesvirus 1

Equid herpesvirus 1

Equid herpesvirus 2

Avian viral diseases such as Marek's disease and the like are preventedand/or treated by compounds of the present invention by methodswell-known in the veterinary art such as by injecting the birds with thecomposition containing the compound, or by adding the compound of theinstant invention to feed or drinking water.

Fish which are in a confined area such as a pool, aquarium or holdingtank may also be treated for viral infections such as herpeslikeviruses, e.g., channel catfish virus (CCV), herpes-virus salomones,Nerka virus and the like by adding the compound directly to the water ofthe pool, aquarium or holding tank or by incorporating the compoundsinto the feed.

The exact regimen for administration of the compounds and compositionsdisclosed herein will necessarily be dependent upon the needs of theindividual subject being treated, the type of treatment and, of course,the judgement of the attending practitioner.

PREPARATION

The compounds of formula (I) may be prepared from compounds of formula(X) (infra) and compounds of formula (XIV) wherein A is hydrogen (infra)which compounds are prepared by Reaction Sequence Ib. Intermediate offormula (V), which is used in Reaction Sequence Ib, is prepared byReaction Sequence Ia. ##STR7## wherein A is hydrogen or acetyl and R³and R⁶ are defined in the following table:

    ______________________________________                                                     R.sup.3    R.sup.6                                               ______________________________________                                        (a)            NH.sub.2     OR                                                (b)            NH.sub.2     SH                                                (c)            N.sub.3      N.sub.3                                           (d)            NH.sub.2     NH.sub.2                                          (e)            Cl           NH.sub.2                                          (f)            N.sub.3      NH.sub.2                                          (g)            NH.sub.2     H                                                 (h)            H            NH.sub.2                                          (i)            H            SH                                                (j)            SH           NH.sub.2                                          ______________________________________                                    

In Reaction Sequence Ia, the compound of formula (III) is prepared byadding epichlorohydrin (II) dropwise to a solution of an alkali metalsalt, preferably the sodium salt, of optionally substituted benzylalcohol in a solvent such as dimethylformamide, dimethylacetamide,hexamethylphosphoramide, dimethylsulfoxide, sulfolane, tetrahydrofuran,and dioxane at a temperature of about 0° C. to 100° C., preferably atabout 15° C. to 40° C. The reaction mixture is stirred for about 10hours to 24 hours, preferably for about 12 hours to 18 hours at atemperature of about 0° C. to 100° C., preferably from about 20° C. to50° C.

Compound of formula (III) is chloromethylated to compound of formula(IV) by bubbling dry hydrogen chloride gas in a solution of the compoundand paraformaldehyde dissolved in a halogenated hydrocarbon solvent suchas dichloroethane, chloroform, dichloromethane, or 1,1,2-trichloroethanecooled to a temperature of about 0° C. to 25° C., preferably at atemperature of about 0° C. The hydrogen chloride gas is added over 30minutes to 3 hours, preferably over 1 hour to 2 hours until theparaformaldehyde dissolves. The solution is held at a temperature fromabout 0° C. to 10° C. for about 12 hours to 48 hours, preferably fromabout 0° C. to 5° C. for about 16 hours to 24 hours.

Compound of formula (V) is prepared by reacting an alkali metal acetatesuch as sodium acetate with compound of formula (IV) dissolved in asolvent such as dimethylformamide, tetrahydrofuran, dimethylacetamide,hexamethylphosphoramide, dimethylsulfoxide, sulfolane, and dioxane at atemperature of about 0° C. to 45° C., preferably from about 0° C. to 25°C. The solution is stirred from about 5 to about 24 hours, preferablyfrom about 10 hours to about 18 hours at a temperature of about 10° C.to about 30° C., preferably at a temperature of about 15° C. to 25° C.

In Reaction Sequence Ib, compound of formula (VII) is prepared byheating guanine (VI) with acetic anhydride, neat, at reflux for about 10to 24 hours, preferably for about 12 to 18 hours.

N²,9-Diacetylguanine of formula (VII) is reacted with compound offormula (V) to form compound of formula (VIII) neat or in a solvent suchas dioxane, sulfolane and the like in the presence of a catalytic amountof an acid such as bis(p-nitrophenyl)phosphate, toluenesulfonic acid,methylphosphonic acid or dichloroacetic acid, preferablybis(p-nitrophenyl)phosphate at a temperature of about 75° C. to 200° C.,preferably at about 110° C. to 180° C. The reaction is generally carriedout using 0.8 moles to 1.2 moles of compound of formula (V) to one moleof compound of formula (VII).

The benzyl protecting groups are removed from compound of formula (VIII)by catalytic hydrogenation to form compound of formula (IX). A catalystsuch as palladium on carbon in a slurry is added to a solution ofcompound of formula (VIII) dissolved in a solvent such as aqueousmethanol. Hydrogen is added to the solution at a pressure of 15 psi to200 psi, preferably at a pressure of 30 psi to 80 psi.

Compound of formula (X) is prepared by deacetylating compound of formula(IX) with a base such as ammonia dissolved in an alcohol such asmethanol. A solution of compound of formula (IX) and the base is stirredfor about 5 hours to 36 hours, preferably for about 10 hours to 24 hoursat a temperature of about 10° C. to 30° C., preferably at a temperatureof about 15° C. to 25° C.

Compound of formula (X) may be esterified to the diacetate of formula(XI) by reacting compound of formula (X) with excess acetic anhydride,either neat or in a solvent such as dimethylformamide, dimethylacetamideand the like at room temperature for two to three days.

Compound of formula (XII) may be prepared by reacting compound offormula (XI) with phosphorus oxychloride according to the methoddescribed in J. Org. Chem. 28:945, 1963. Compound of formula (XI) isadded to a solution of phosphorus oxychloride in N,N-diethylaniline atroom temperature. The suspension is heated at reflux for 2 to 30minutes, preferably from 2 to 5 minutes. The excess phosphorusoxychloride is removed and the product recovered by conventional meanssuch as extraction with an organic solvent followed by chromatography.

Compound of formula (XII) may be further chlorinated by forming thediazo salt with sodium nitrite in hydrochloric acid as described in J.Org. Chem. 31:3258, 1966. To compound of formula (XII) in aqueoushydrochloric acid is added sodium nitrite in water at 0° to 5° C. Thesolution is diluted with water and the excess hydrochloric acid isneutralized with aqueous ammonia and compound of formula (XIII) isrecovered by methods well known in the art such as extraction with anorganic solvent followed by chromatography.

Compounds of formula (XIV) may be prepared from compounds of formulas(XII) and (XIII) by methods well known in the art. See, for example,"Heterocyclic Compounds--Fused Pyrimidines Part II Purines, Ed. D. J.Brown (1971) Wiley-Interscience" and U.S. Pat. No. 4,199,574 whichpatent is incorporated herein by reference. See preceding table forcompounds of formula (XIV)a-j.

Compound of formula (XIVb) wherein A is hydrogen may be prepared byreacting a compound of formula (XII) with thiourea dissolved in asolvent such as isopropanol with heating at reflux for one to two hours.The thiourea adduct which forms is broken down with an alkali such asaqueous ammonia yielding the thio compound. The reaction also leads tothe hydrolysis of the ester groups.

Compounds of formula (XIVa) wherein A is hydrogen and R is lower alkylare prepared from compound of formula (XII) by treatment with analcoholic solution of the appropriate alkali metal alkoxide such assodium methoxide in methanol at room temperature or with mild heating.

Various compounds of formula (XIV) may be prepared from compound offormula (XIII). For example, compound of formula (XIVc) wherein A isacetyl is prepared by treating compound of formula (XIII) with sodiumazide in a solvent such as ethanol:water, dimethylformamide,hexamethylphosphoramide and the like. The reactants are heated for twoto 24 hours at 80° to 200° C. Compound of formula (XIVd), wherein A ishydrogen, are prepared by hydrogenating compound of formula (XIVc)using, for example, a palladium on charcoal catalyst.

Compound of formula (XIII) is converted to compound of formula (XIVe)wherein A is hydrogen by heating compound of formula (XIII) and ammoniadissolved in methanol in a bomb for 16 to 24 hours at 85° to 110° C. Theabove compound may be further ammoniated by heating compound of formula(XIVe) dissolved in liquid ammonia in a bomb for 24 to 48 hours at 110°to 150° C. to form compound of formula (XIVd) wherein A is hydrogen.

Another method of preparing compound of formula (XIVd) is by treatingcompound of formula (XIVe) with hydrazine and then with a cold solutionof sodium nitrite to form compound of formula (XIVf) wherein A ishydrogen, which in turn is hydrogenated to the compound of formula(XIVd) using, for example, a palladium on charcoal catalyst.

The amino groups of compounds of formula (XIV) wherein R³ and/or R⁶ isamino may be alkylated to the secondary or tertiary amines by treatmentwith an alkyl halide such as methyl iodide. A preferred method forpreparing the above alkylated amino compounds is by reacting a compoundof formula (XIII) or (XIVe) with an alkyl or dialkyl amine.

Those compounds of formula (XIV) wherein A is acetyl may be hydrolyzedby methods well known in the art such as by acidic or basic hydrolysis.

Compounds of formulas (XIVg) and (XIVh) may be prepared by thehydrogenation of compounds of formulas (XII) and (XIVe) respectivelyusing a hydrogenation catalyst such as palladium in the presence of abase such as magnesium dioxide.

Compound of formula (XIVi) wherein A is hydrogen is prepared by reactingcompound of formula (XIVh) with sodium nitrite in acetic acid to formthe 6-keto compound which in turn is chlorinated with a chlorinatingagent such as phosphoryl chloride, phosphorous pentachloride and thelike by methods well known in the art. The 6-chloro intermediate istreated with thiourea as described above.

Compounds of formula (XIVj) may be prepared, for example, by reactingcompound of formula (XIVe) with methanolic hydrogen sulfide-ammoniumcarbonate as described in J. Org. Chem., 39(9):1256, 1974 or with sodiummercaptide in dimethylformamide as described in J. Med. Chem.,16(12):1381, 1973.

Compounds of formula (XIV) wherein R³ or R⁶ is thio may be alkylatedwith an alkyl halide such as an alkyl iodide in a solvent such as analkanol at room temperature.

The following compounds of formula (XIV) wherein A is hydrogen, forexample, may be prepared by one or a combination of the methodsdiscussed above:

2-amino-6-methoxy-9-(1,3-dihydroxy-2-propoxymethyl)purine;

2-methylamino-6-ethoxy-9-(1,3-dihydroxy-2-propoxymethyl)purine;

2-amino-6-thio-9-(1,3-dihydroxy-2-propoxymethyl)purine;

2-n-butylamino-6-thio-9-(1,3-dihydroxy-2-propoxymethyl)purine;

2-amino-6-methylthio-9-(1,3-dihydroxy-2-propoxymethyl)purine;

2-dimethylamino-6-methylthio-9-(1,3-dihydroxy-2-propoxymethyl)purine;

2,6-diazido-9-(1,3-dihydroxy-2-propoxymethyl)purine;

2,6-diamino-9-(1,3-dihydroxy-2-propoxymethyl)purine;

2-methylamino-6-amino-9-(1,3-dihydroxy-2-propoxymethyl)purine;

2-amino-6-methylamino-9-(1,3-dihydroxy-2-propoxymethyl)purine;

2,6-di(methylamino)-9-(1,3-dihydroxy-2-propoxymethyl)purine;

6-chloro-2-amino-9-(1,3-dihydroxy-2-propoxymethyl)purine;

2-chloro-6-methylamino-9-(1,3-dihydroxy-2-propoxymethyl)purine;

2-azido-6-ethylamino-9-(1,3-dihydroxy-2-propoxymethyl)purine

2-amino-9-(1,3-dihydroxy-2-propoxymethyl)purine;

2-methylamino-9-(1,3-dihydroxy-2-propoxymethyl)purine;

2-dimethylamino-9-(1,3-dihydroxy-2-propoxymethyl)purine;

6-amino-9-(1,3-dihydroxy-2-propoxymethyl)purine;

6-methylamino-9-(1,3-dihydroxy-2-propoxymethyl)purine;

6-dimethylamino-9-(1,3-dihydroxy-2-propoxymethyl)purine;

6-thio-9-(1,3-dihydroxy-2-propoxymethyl)purine;

6-methylthio-9-(1,3-dihydroxy-2-propoxymethyl)purine; and

6-amino-2-thio-9-(1,3-dihydroxy-2-propoxymethyl)purine.

Compounds of formula (I) wherein R¹ and/or R² are --C(Y)OR⁷ may beprepared by forming an intermediate of formula (XV) (supra) wherein W ishydrogen or 1-carbonylimidazole and Wa is 1-carbonylimidazole or whereinW is hydrogen or 1-thiocarbonylimidazole and Wa is1-thiocarbonylimidazole and reacting the intermediate with R⁷ OH whereinR⁷ is as defined above. When Y is oxygen, compounds of formula (X) or(XIV), wherein A is hydrogen, and 1,1'-carbonyldiimidazole, in a molarratio of 1:10, preferably 1:3-5, are reacted with stirring in a solventsuch as N,N-dimethylformamide, N,N-dimethylacetamide,N-methylpyrrolidine, hexane, acetonitrile, tetrahydrofuran, toluene andthe like at room temperature to 70° C., preferably at 45° to 65° C. for9 to 24 hours, preferably for 15 to 20 hours. After the removal of thesolvent, the intermediate which may be a mixture of the mono and dicarbonylimidazole of formula (XV) is reacted with the appropriatealcohol or amine, optionally in the presence of a catalyst such as4-dimethylaminopyridine, with heating to 50° to 200° C., preferably from75° to 125° C. for 12 to 48 hours, preferably for 18 to 36 hours.Compounds of formula (I) are isolated by methods well known in the artsuch as chromatography. Chromatography may also be used to separate themonocarbonate of formula (I) from the dicarbonate of formula (I). When Yis sulfur 1,1'carbonyldiimidazole is replaced with1,1'-thiocarbonyldiimidazole in the above procedure.

1,1'-Carbonyldiimidazole is available from, i.a., Aldrich Chemical Co.The alcohols and amines used in the reaction are available or if notavailable may be prepared by methods well known in the art such as thealcohols may be prepared by reduction of the corresponding aldehyde orthe amines may be prepared by the reduction of the corresponding nitrocompound or by the reaction of ammonia with the appropriate hydrocarbonhalide.

An alternative method for preparing the compounds of formula (I) whereinR¹ and/or R² are --C(O)OR⁷ is by reacting compounds of formula (X) or(XIV) wherein A is hydrogen with (R⁷ OC(O))₂ O. The reactants in asolvent such as dimethylformamide and the like, in the presence of acatalyst such as 4-dimethylaminopyridine are stirred at room temperatureto 50° C., preferably at room temperature, for 1 to 5 days, preferablyfor 11/2 to 4 days. Compounds of formula (I) are isolated byconventional methods such as chromatography.

Another method for preparing the compounds of formula (I) wherein R¹and/or R² are --C(O)OR⁷ for all values of R⁷ is by first treatingcompound of formula (XI) or (XIV) wherein A is acetyl and R³ and/or R⁶is amino with a trityl protecting agent such as triphenylmethyl chloride(trityl chloride), 4-methoxyphenyldiphenylmethyl chloride(mono-methoxytritylchloride) and the like. The trityl protecting agentsare readily available from, i.a., Aldrich Chemical Co.. The reactants ina solvent such as dimethylformamide, pyridine, and the like with acatalyst e.g., 4-dimethylaminopyridine are heated at 40° to 70° C.,preferably at 45° to 60° C. for 8 to 24 hours, preferably for 12 to 18hours. The amino protected compound is isolated by conventional meanssuch as crystallization and the acetate groups are hydrolyzed with abase, such as an alkali metal hydroxide, e.g., sodium hydroxide andpotassium hydroxide, or with ammonium hydroxide. The dihydroxy compoundand a catalyst such as 4-dimethylaminopyridine in pyridine is addeddropwise to the appropriate hydrocarbyloxycarbonyl chloride either neator in a solvent such as methylene chloride, dichloroethane and the like.The reactants are stirred at room temperature for 10 to 24 hours,preferably from 12 to 18 hours. The product is isolated by methods wellknown in the art such as chromatography. The amino protective groups areremoved by treatment with an organic acid such as glacial acetic acid,trifluoroacetic acid, benzenesulfonic acid and the like with heatingfrom room temperature to 100° C., preferably from 40° to 80° C. for oneto twelve hours, preferably from one to five hours. The product isisolated by chromatography or crystallization.

The amino group(s) of the above described compound of formulas (XI) and(XIV) may also be protected by reacting the compounds with the acetal ofN,N-dimethyl formamide available from, i.a., Aldrich Chemical Co. andthen proceeding as discussed above.

The hydrocarbyloxycarbonyl chlorides are readily available or if notreadily available may be prepared by reacting phosgene with theappropriate alcohol under reaction conditions well known in the art.

The monocarbonates of formula (I) may be prepared by reacting compoundsof formula (X) or (XIV) wherein A is hydrogen with a trityl protectivegroup as defined supra. The protective group reacts with the aminonitrogen if present and one hydroxy group. The unprotected hydroxy groupis reacted with a hydrocarbyloxycarbonyl chloride by the methoddescribed supra. The protective groups are removed as describedhereinabove.

Compounds of formula (I) wherein R³ and/or R⁶ are NHC(O)R⁸ may beprepared by heating compound of formula (I) wherein R³ and/or R⁶ isamino with the appropriate acid chloride in a solvent such as pyridinefrom 35° to 100° C., preferably from 50°-60° C. for 6 to 24 hours,preferably for 12 to 18 hours.

The following specific description is given to enable those skilled inthe art to more clearly understand and practice the invention. It shouldnot be considered as a limitation upon the scope of the invention butmerely as being illustrative and representative thereof.

PREPARATION I Preparation of 1,3-Di-O-benzylglycerol

Sodium hydride (100 g (50% dispersion in mineral oil), 2.08 mol) waswashed twice with 1 l of hexane then dried under nitrogen. Drydimethylformamide (1.5 l) was added. Benzyl alcohol (400 ml) was thenadded at such a rate to keep the temperature below 50° C. The additiontook 2 hours. Epichlorohydrin (92.5 g, 1 mol) was then added dropwiseover 0.5 hour with ice cooling in order to keep the temperature below40° C. The solution was next stirred for 16 hours at 21° C. then for 2.5hours at 50° C. The dimethylformamide was then removed by evaporation atreduced pressure. The oily residue was dissolved in 2.5 l diethyl ether.The organic solution was washed with 2 l of water, 2 l of 2%hydrochloric acid, 2 l of 1% sodium bicarbonate, and 1 l of brine, driedover sodium sulfate, and concentrated to a brown oil. Distillation gave147.8 g of 1,3-di-O-benzylglycerol (bp 170°-180° C./1 torr).

PREPARATION II Preparation of 1,3-Di-O-benzyl-2-O-chloromethylglycerol

Dry hydrogen chloride gas was bubbled for 1.5 hours into a solution of1,3-di-O-benzylglycerol from Preparation I (15 g, 55 mmol) andparaformaldehyde (3.3 g, 110 mmol) in 175 ml of 1,2-dichloroethane at 0°C. The solution was then stored in a stoppered flask for 21 hours at 4°C. Next, the solution was dried over magnesium sulfate with warming to21° C. then filtered and concentrated to give 17.5 g of1,3-di-O-benzyl-2-O-chloromethylglycerol.

PREPARATION III Preparation of 2-O-Acetoxymethyl-1,3-di-O-benzylglycerol

To a solution of 1,3-di-O-benzyl-2-O-chloromethylglycerol fromPreparation II (17.5 g, 55 mmol) in 400 ml of dimethlyformamide at 0° C.under a drying tube was added sodium acetate (6 g). The solution wasthen warmed to 21° C. and magnetically stirred for 15 hours. The solventwas removed by evaporation at reduced pressure and the oily residuedissolved in 1 pound of diethylether. The ether solution was washed oncewith 750 ml of water, two times with 250 ml of water, and once with 250ml of brine, dried over sodium sulfate and concentrated to give 19 g of2-O-acetoxymethyl-1,3-di-O-benzylglycerol as an oil.

PREPARATION IV Preparation of N²,9-Diacetylguanine

Guanine (20 g, 0.132 mol) was combined with 300 ml of acetic anhydrideand the mixture heated at reflux for 16 hours. The mixture was cooledand the excess acetic anhydride removed by evaporation at reducedpressure. The residue was recrystallized from dimethyl sulfoxide to give25.6 g of N²,9-diacetylguanine.

PREPARATION V A. Preoaration of N²-Acetyl-9-(1,3-dibenzvloxy-2-propoxymethyl)guanine

N²,9-Diacetylguanine from Preparation IV (15.61 g, 66 mmol),2-O-acetoxymethyl-1,3-di-O-benzylglycerol from Preparation III (19 g, 55mmol), and bis(p-nitrophenyl)phosphate (0.5 g) were stirred togetherwith 150 ml of diethylether. The solvent was removed by evaporation andthe residue heated in a 175° C. oil bath for 1.5 hours under a stream ofnitrogen. Column chromatography eluting with 1:9 methanol/methylenechloride followed by recrystallization from ethyl acetate afforded 4.76g of N² -acetyl-9-(1,3-dibenzyloxy-2-propoxymethyl)guanine, mp 145°-146°C.

B. Preparation of N² -Acetyl-9-(1,3-dihydroxy-2-propoxymethyl)guanine

To a solution of N² -acetyl-9-(1,3-dibenzyloxy-2-propoxymethyl)guanine(4.62 g, 9.67 mmol) in 150 ml of methanol plus 40 ml of water was added20% palladium hydroxide on carbon as a slurry in 10 ml of water. Themixture was hydrogenated on a Parr hydrogenator at 60 psi of hydrogenfor 38 hours then filtered through celite and concentrated to a whitesolid. Recrystallization from methanol/ethyl acetate gave 1.4 g of N²-acetyl-9-(1,3-dihydroxy-2-propoxymethyl)guanine, mp 205°-208° C.

The mother liquor was further reduced with 10% palladium on carbon (1 g)in 150 ml of methanol plus 50 ml of water at 50 psi for 47 hours. Thetotal yield of N² -acetyl-9-(1,3-dihydroxy-2-propoxymethyl)guanine was2.11 g.

C. Preparation of 9-(1,3-Dihydroxy-2-propoxymethyl)-guanine

N² -Acetyl-9-(1,3-dihydroxy-2-propoxymethyl)guanine (721.9 mg, 2.4 mmol)was stirred with 50 ml of methanolic ammonia solution (methanolsaturated with ammonia at 0° C.) for 17 hours at 21° C. The solution wasconcentrated to a white solid and the residue recrystallized from wateror methanol to give 582.3 mg of9-(1,3-dihydroxy-2-propoxymethyl)guanine, mp 250° C. d.

EXAMPLE 1 9-[1,3-Di(methoxycarbonyloxy)-2-propoxymethyl]guanine

A solution of 1.509 g of 9-(1,3-dihydroxy-2-propoxymethyl)guanine and3.0 g of 1,1'-carbonyldiimidazole in 150 ml of dry dimethylformamide wasstirred under a drying tube at 55° C. for 16 hours. A white precipitatedeveloped. The dimethylformamide was removed at reduced pressure and theresidue was treated with 200 ml of methanol at reflux for 2 hours undera drying tube. The solution was then cooled to 0° C. and filtered. Theresidue was recrystallized from methanol to give 1.576 g of9-[1,3-di(methoxycarbonyloxy)-2-propoxymethyl]guanine, m.p. 204°-206° C.

EXAMPLE 2 A.9-[1,3-Di(cyclopentyloxycarbonyloxy)-2-propoxymethyl]guanine

A solution of 0.50 g of 9-(1,3-dihydroxy-2-propoxymethyl)guanine and 1.6g of 1,1'-carbonyldiimidazole in 75 ml of dry dimethylformamide wasstirred under a drying tube at 55° C. for 17 hours. Thedimethylformamide was removed at reduced pressure. The residue wastreated with 20 ml of cyclopentanol and 50 mg of 4-dimethylaminopyridineand heated at 100° C. for 19 hours. The solution was concentrated andthe residue chromatographed over silica gel eluting with a gradient of1/9 to 1/5 methanol/methylene chloride to give 495 mg of9-[1,3-di(cyclopentyloxycarbonyloxy)-2-propoxymethyl]guanine in thefirst cut which was recrystallized from methanol to give 0.37 g of theproduct, m.p. 211.5°-214° C.

B. Similarly, using the procedure in Example 1 or 2(A) substituting theappropriate alcohol for methanol or cyclopentanol and using theappropriate compound of formula (XIV), wherein A is hydrogen, thefollowing compounds are prepared:

2-amino-6-methoxy-9-[1,3-di(ethoxycarbonyloxy)-2-propoxymethyl]purine;

2-methylamino-6-ethoxy-9-[1,3-di(n-propoxycarbonyloxy)-2-propoxymethyl]purine;

2-amino-6-thio-9-[1,3-di(n-butoxycarbonyloxy)-2-propoxymethyl]purine;

2-n-butylamino-6-thio-9-[1,3-di(n-hexyloxycarbonyloxy)-2-propoxymethyl]purine;

2-amino-6-methylthio-9-[1,3-di(n-octyloxycarbonyloxy)-2-propoxymethyl]purine;

2-dimethylamino-6-methylthio-9-[1,3-di(n-decyloxycarbonyloxy)-2-propoxymethyl]purine;

2,6-diazido-9-[1,3-di(ethenyloxycarbonyloxy)-2-propoxymethyl]purine;

2,6-diamino-9-[1,3-di(but-4-enyloxycarbonyloxy)-2-propoxymethyl]purine;

2-methylamino-6-amino-9-[1,3-di(oct-6-enyloxycarbonyloxy)-2-propoxymethyl]purine;

2-amino-6-methylamino-9-[1,3-di(dec-8-enyloxycarbonyloxy)-2-propoxymethyl]purine;

2,6-di(methylamino)-9-[1,3-di(cyclopentyloxycarbonyloxy)-2-propoxymethyl]purine;

6-chloro-2-amino-9-[1,3-di(cyclohexyloxycarbonyloxy)-2-propoxymethyl]purine

2-chloro-6-methylamino-9-[1,3-di(phenoxycarbonyloxy)-2-propoxymethyl]purine;

2-azido-6-ethylamino-9-[1,3-di(benzyloxycarbonyloxy)-2-propoxymethyl]purine

2-amino-9-[1,3-di(methoxycarbonyloxy)-2-propoxymethyl]purine;

2-methylamino-9-[1,3-di(ethoxycarbonyloxy)-2-propoxymethyl]purine;

2-dimethylamino-9-[1,3-di(n-propoxycarbonyloxy)-2-propoxymethyl]purine;

6-amino-9-[1,3-di(n-butoxycarbonyloxy)-2-propoxymethyl]purine;

6-methylamino-9-[1,3-di(n-pentyloxycarbonyloxy)-2-propoxymethyl]purine;

6-dimethylamino-9-[1,3-di(n-hexyloxycarbonyloxy)-2-propoxymethyl]purine;

6-thio-9-[1,3-di(n-octyloxycarbonyloxy)-2-propoxymethyl]purine;

6-methylthio-9-[1,3-di(n-decyloxylcarbonyloxy)-2-propoxymethyl]purine;

6-amino-2-thio-9-[1,3-di(ethenyloxycarbonyloxy)-2-propoxymethyl]purine;and

9-[1,3-di(n-octyloxycarbonyloxy)-2-propoxymethyl]guanine.

EXAMPLE 3 9-[1,3-Di(t-butoxycarbonyloxy)-2-propoxymethyl]guanine

A solution of 212 mg of 9-(1,3-dihydroxy-2-propoxymethyl)guanine and 56mg of 4-dimethylaminopyridine in 5 ml of di-t-butyldicarbonate plus 10ml of N,N'-dimethylformamide was stirred in a stoppered flask for 72hours. The solution was then concentrated and the residuechromatographed (1/7 methanol/methylene chloride) to give 35.8 mg of9-[1,3-di(t-butoxycarbonyloxy)-2-propoxymethyl]guanine followingrecrystallization from methanol, m.p. 192°-193° C.

EXAMPLE 4 9-(1,3-benzyloxycarbonyloxy-2-propoxymethyl)guanine

A mixture of 3.00 g of 9-(1,3-dihydroxy-2-propoxymethyl)guanine, 300 mgof 4-dimethylaminopyridine, and 100 ml of acetic anhydride wasvigorously stirred for 3 days at room temperature. The acetic anhydridewas removed by evaporation at reduced pressure and the residuerecrystallized from methanol to give 3.62 g of9-(1,3-diacetyloxy-2-propoxymethyl)guanine, m.p. 237°-239° C.

A solution of 3.3 g of 9-(1,3-diacetoxy-2-propoxymethyl)guanine, 7.0 gof 4-methoxyphenyldiphenylmethyl chloride, 7.0 ml of triethylamine and300 mg of 4-dimethylaminopyridine in 50 ml of dry dimethylformamide washeated with magnetic stirring at 50° C. for 15 hours. Methanol (5 ml)was added. The solution was then concentrated at reduced pressure to abrown oil which was chromatograohed over silica gel eluting with 1:12methanol:methylene chloride to give an oil. The oil was crystallizedfrom ethyl acetate:hexane to give 5.42 g of N²-(4-methoxyphenyldiphenylmethyl)-9-(1,3-diacetoxy-2-propoxymethyl)guanine,m.p. 139°-141° C.

4.0 G of N²-(4-methoxyphenyldiphenylmethyl)-9-(1,3-diacetoxy-2-propoxymethyl)guaninein 100 ml of methanol plus 20 ml of concentrated ammonium hydroxide wasmagnetically stirred at 22° C. for 16 hours then at 50° C. for 2.5hours. An additional 10 ml of ammonium hydroxide were then added and thesolution stirred another 2.5 hours at 50° C. Next, the solution wasconcentrated at reduced pressure and the residual solid recrystallizedfrom methanol:ethyl acetate to give 3.5 g of N²-(4-methoxyphenyldiphenylmethyl)-9-(1,3-dihydroxy-2-propoxymethyl)guanine,m.p. 148°-151° C.

To a solution of N²-(4-methoxyphenyldiphenylmethyl-9-(1,3-dihydroxy-2-propoxymethyl)guanine(0.25 g), in pyridine (5 ml) at room temperature was addedbenzyloxycarbonylchloride (0.34 g) in 5 ml of dichloromethane. After 16hours, the solution was evaporated and the residue chromatographed oversilica gel (15% methanol in methylene chloride). Fraction A wasrecovered and the solvent evaporated to yield 150 mg of N²-(4-methoxyphenyldiphenylmethyl)-9-[1,3-di(benzyloxycarbonyloxy)-2-propoxymethyl]guaninewhich was recrystallized from methanol, m.p. 152°-155° C. Fraction B wasrecovered and the solvent evaporated to yield 60 mg of N²-(4-methoxyphenyldiphenylmethyl)-9-(1-hydroxy-3-benzyloxycarbonyloxy-2-propoxymethyl)guaninewhich was recrystallized from methanol, m.p. 193°-198° C.

The 4-methoxyphenyldiphenylmethyl group is removed by treatment with anorganic acid such as glacial acetic acid to yield9-[1,3-di(benzyloxycarbonyloxy)-2-propoxymethyl]guanine and9-(1-hydroxy-3-benzyloxycarbonyloxy-2-propoxymethyl)guaninerespectively.

EXAMPLE 5 A. 9-(1-Hydroxy-3-methoxycarbonyloxy-2-propoxymethyl)guanine

A solution of 84.5 mg of 9-(1,3-dihydroxy-2-propoxymethyl)guanine and 65mg of 1',1'-carbonyldiimidazole in 5 ml of N,N-dimethylformamide washeated at 45° C. for 21 hours. The dimethylformamide was removed atreduced pressure and the residue boiled with methanol. The solution wasconcentrated and the residue chromatographed over silica gel elutingwith a gradient of 1/7 to 1/4 methanol/methylene chloride. The firstcompound to elute was recrystallized from methanol to give 18.7 mg of9-[1,3-di(methoxycarbonyloxy)-2-propoxymethyl]guanine.9-(1-Hydroxy-3-methoxycarbonyloxy-2-propoxymethyl)guanine, which waseluted in the second cut, was recrystallized from methanol to give 26 mgof the product, m.p. 189°-190° C.

B. Similarly, using the above procedure in Part A substituting theappropriate alcohol for methanol and using the appropriate compound offormula (XIV) wherein A is hydrogen the following compounds areprepared:

2-amino-6-methoxy-9-(1-hydroxy-3-methoxycarbonyloxy-2-propoxymethyl)purine;

2-methylamino-6-ethoxy-9-(1-hydroxy-3-ethoxycarbonyloxy-2-propoxymethyl)purine;

2-amino-6-thio-9-(1-hydroxy-3-n-propoxycarbonyloxy-2-propoxymethyl)purine;

2-n-butylamino-6-thio-9-(1-hydroxy-3-n-butoxycarbonyloxy-2-propoxymethyl)purine;

2-amino-6-methylthio-9-(1-hydroxy-3-n-hexyloxycarbonyloxy-2-propoxymethyl)purine;

2-dimethylamino-6-methylthio-9-(1-hydroxy-3-n-octyloxycarbonyloxy-2-propoxymethyl)purine;

2,6-diazido-9-(1-hydroxy-3-n-decyloxylcarbonyloxy-2-propoxymethyl)purine;

2,6-diamino-9-(1-hydroxy-3-ethenyloxycarbonyloxy-2-propoxymethyl)purine;

2-methylamino-6-amino-9-(1-hydroxy-3-but-4-enyloxycarbonyloxy-2-propoxymethyl)purine;

2-amino-6-methylamino-9-(1-hydroxy-3-oct-6-enyloxycarbonyloxy-2-propoxymethyl)purine;

2,6-di(methylamino)-9-(1-hydroxy-3-dec-8-enyloxycarbonyloxy-2-propoxymethyl)purine;

6-chloro-2-amino-9-(1-hydroxy-3-cyclopentyloxycarbonyloxy-2-propoxymethyl)purine;

2-chloro-6-methylamino-9-(1-hydroxy-3-cyclohexyloxycarbonyloxy-2-propoxymethyl)purine;

2-azido-6-ethylamino-9-(1-hydroxy-3-cyclohexyloxycarbonyloxy-2-propoxymethyl)purine;

2-amino-9-(1-hydroxy-3-phenoxycarbonyloxy-2-propoxymethyl)purine;

2-methylamino-9-(1-hydroxy-3-benzyloxylcarbonyloxy-2-propoxymethyl)purine;

2-dimethylamino-9-(1-hydroxy-3-methoxycarbonyloxy-2-propoxymethyl)purine;

6-amino-9-(1-hydroxy-3-methoxycarbonyloxy-2-propoxymethyl)purine;

6-methylamino-9-(1-hydroxy-3-ethoxycarbonyloxy-2-propoxymethyl)purine;

6-dimethylamino-9-(1-hydroxy-3-n-propoxycarbonyloxy-2-propoxymethyl)purine;

6-thio-9-(1-hydroxy-3-n-butoxycarbonyloxy-2-propoxymethyl)purine;

6-methylthio-9-(1-hydroxy-3-n-hexyloxycarbonyloxy-2-propoxymethyl)purine;and

6-amino-2-thio-9-(1-hydroxy-3-n-octyloxylcarbonyloxy-2-propoxymethyl)purine.

EXAMPLE 6 A. 9-[1,3-Di(ethylaminocarbonyloxy)-2-propoxymethyl]guanine

A mixture of 0.500 g of 9-(1,3-hydroxy-2-propoxymethyl)guanine 1.588 gof 1,1'-carbonyldiimidazole, and 50 ml of N,N-dimethylformamide wasstirred vigorously for 3.5 hours at 100° C. 15 Ml of 33% aqueousethylamine was then added. After two hours the reaction mixture wasconcentrated at reduced pressure then chromatographed over silica geleluting with 1/9 methanol/methylene chloride to give9-[1,3-di(ethylaminocarbonyloxy)-2-propoxymethyl]guanine which wasrecrystallized to afford 0.33 g of the product, m.p. 198°-200° C.

B. Similarly, using the procedure as above in Part A substituting theappropriate amine for ethylamine and using the appropriate compound offormula (XIV), wherein A is hydrogen, the following compounds areprepared:

2-amino-6-methoxy-9-[1,3-di(methylaminocarbonyloxy)-2-propoxymethyl]purine;

2-methylamino-6-ethoxy-9-[1,3-(n-butylaminocarbonyloxy)-2-propoxymethyl]purine;

2-amino-6-thio-9-[1,3-di(n-hexylaminocarbonyloxy)2-propoxymethyl]purine;

2-n-butylamino-6-thio-9-[1,3-di(n-octylaminocarbonyloxy)-2-propoxymethyl]purine;

2-amino-6-methylthio-9-[1,3-di(n-dodecylamino-2-propoxymethyl]purine;

2-dimethylamino-6-methylthio-9-[1,3-di(ethenylaminocarbonyloxy)-2-propoxymethyl]purine;

2,6-diazido-9-[1,3-di(cyclohexylaminocarbonyloxy)-2-propoxymethyl]purine;and

2,6-diamino-9-[1,3-di(phenylaminocarbonyloxy)-2-propoxymethyl]purine.

EXAMPLE 7 A. 9-[1,3-Di(methoxythiocarbonyloxv)-2-propoxymethyl]guanine

A solution of 9-(1,3-dihydroxy-2-propoxymethyl)guanine (50 mg) and1,1-thiocarbonyldiimidazole (175 mg) in 6 ml of dimethylformamide washeated at 50° C. for 16 hours. The dimethylformamide was evaporated atreduced pressure and the residue treated with methanol and a catalyticamount of 4-dimethylaminopyridine for 24 hours at room temperature. Thesolution was concentrated and the residue was chromatographed (1:5methanol-methylene chloride) to give 10 mg of9-[1,3-di(methoxythiocarbonyloxy)-2-propoxymethyl]guanine, m.p.148°-150° C.

B. Similarly, using the above procedure in Part A substituting theappropriate alcohol for methanol and using compound of formula (XIV),wherein A is hydrogen, the following compounds are prepared:

2-methylamino-6-amino-9-[1,3-di(n-propoxythiocarbonyloxy)-2-propoxymethyl]purine;

2-amino-6-methylamino-9-[1,3-di(n-butoxythiocarbonyloxy)-2-propoxymethyl]purine;

2,6-di(methylamino)-9-[1,3-di(n-octyloxythiocarbonyloxy)-2-propoxymethyl]purine;

6-chloro-2-amino-9-[1,3-di(n-decyloxythiocarbonyloxy)-2-propoxymethyl]purine;

2-chloro-6-methylamino-9-[1,3-di(ethenyloxythiocarbonyloxy)-2-propoxymethyl]purine;

2-azido-6-ethylamino-9-[1,3-di(2-propenyloxythiocarbonyloxy)-2-propoxymethyl)purine;

2-amino-9-[1,3-di(cyclopentyloxythiocarbonyloxy)-2-propoxymethyl]purine;and

2-methylamino-9-[1,3-di(benzyloxythiocarbonyloxy)-2-propoxymethyl)purine.

EXAMPLE 8

The following example illustrates the preparation of representativepharmaceutical formulations containing an active compound of formula (I)such as 9-[1,3-di(methoxycarbonyloxy)-2-propoxymethyl]guanine.

    ______________________________________                                         A. Topical Formulation                                                       ______________________________________                                        Active compound          0.2-2  g                                             Span 60                  2      g                                             Tween 60                 2      g                                             Mineral oil              5      g                                             Petrolatum               10     g                                             Methyl paraben           0.15   g                                             Propyl paraben           0.05   g                                             BHA (butylated hydroxy anisole)                                                                        0.01   g                                             Water qs                 100    ml                                            ______________________________________                                    

All of the above ingredients, except water, are combined and heated at60° C. with stirring. A sufficient quantity of water at 60° C. is thenadded with vigorous stirring to provide 100 g of the cream formulationwhich is then cooled to room temperature.

The following formulation is useful for intraperitoneal (IP),subcutaneous (SC) and intramuscular (IM) injection.

    ______________________________________                                         B. IP, SC and IM Formulation                                                 ______________________________________                                        Active compound        0.5    g                                               Tween 80               0.8    g                                               Benzyl alcohol         0.9    g                                               0.9% Saline solution qs                                                                              100    ml                                              ______________________________________                                    

The active compound is finely micronized and added to Tween 80 andbenzyl alcohol with stirring. A sufficient quantity of 0.9% salinesolution is then added with stirring to provide 100 ml of the IP, SC orIM suspension which is filtered through a 0.2 micron membrane filter andpackaged under sterile conditions.

    ______________________________________                                        C. Tablet Formulation                                                                          Parts by weight                                              ______________________________________                                        Active compound    200                                                        Magnesium stearate  3                                                         Starch              30                                                        Lactose            116                                                        PVP (polyvinylpyrrolidone)                                                                        3                                                         ______________________________________                                    

The above ingredients are combined and granulated using methanol as thesolvent. The formulation is then dried and formed into tablets(containing 200 mg of active compound) with an appropriate tablettingmachine.

EXAMPLE 9

The exceptional antiviral activity of the compounds of the invention isillustrated by the following assay procedures:

The Herpes simplex virus 2 strain G for infection is prepared in HEp-2cell cultures. Virus is adsorbed for 1 hour, fresh media is placed onthe cells, and they are incubated at 35° C. until all cells areinfected. The cell suspension is frozen at -70° C., thawed, andcentrifuged to remove cell debris. The supernatant fluid is aliquotedand stored frozen at -70° C. until use. A 10⁶.7 dilution of thesupernatant fluid produces a 50% cell culture infective dose (CCID₅₀) inHEp-2 cells and a 10³.7 dilution produces a 50% lethal challenge (LC₅₀)in mice.

Groups of 20 Swiss Webster female mice (15-17 gm), are challenged byintraperitoneal route using 0.2 ml of EMEM containing 10 LC₅₀ /mouse ofvirus. Mice challenged with 10⁰.5 more or less virus than the 10 LD₅₀challenge serves as a virulence control to assure the model is workingproperly.

Treatment with test compounds begins 6 hours post-challenge. The mice,divided into groups of 20, are administered the compounds in a suitablesaline vehicle s.c. at 5 mg/kg, 10 mg/kg and 20 mg/kg. One group of 20mice is used as a control group and administered the vehicle alone s.c.The treatment is repeated at 24, 48, 72 and 96 hours post-challenge.

Compounds of the instant invention show antiviral activity in the abovetest.

What is claimed is:
 1. A compound of the formula ##STR8## wherein W ishydrogen or 1-carbonylimidazole, Wa is 1-carbonylimidazole or wherein Wis hydrogen or 1-thiocarbonylimidazole and Wa is 1-thiocarbonylimidazoleR³ is hydrogen, halo, thio, lower alkylthio of one to six carbon atoms,azido, NR⁹ R¹⁰ wherein R⁹ and R¹⁰ are independently hydrogen or loweralkyl of one to six carbon atoms or --NHC(O)Rhu 8 wherein R⁸ ishydrogen, alkyl of one to nineteen carbon atoms or 1-adamantyl; and(a)R⁶ is hydrogen, halo, lower alkoxy of one to six carbon atoms, azido,thio, lower alkylthio of one to six carbon atoms, --NR⁹ R¹⁰ wherein R⁹and R¹⁰ are as defined above or --NHC(O)R⁸ wherein R⁸ is as definedabove and R⁴ together with R⁵ is a bond; or (b) R⁵ together with R⁶ is aketo group and R⁴ is hydrogen.
 2. A compound of the formula ##STR9##wherein W is hydrogen or 1-carbonylimidazole and Wa is1-carbonylimidazole or wherein W is hydrogen or 1-thiocarbonylimidazoleand Wa is 1-thiocarbonylimidazole.
 3. A pharmaceutical composition whichcomprises a pharmaceutically acceptable carrier and a compound ofclaim
 1. 4. A method of treating a viral infection in a warm blooded orcold blooded animal having a viral infection which comprisesadministering an effective amount of a compound of claim 1.